Polycystic ovary syndrome, insulin resistance, and obesity: navigating the pathophysiologic labyrinth

Abstract

Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine-metabolic disorder that implies various severe consequences to female health, including alarming rates of infertility. Although its exact etiology remains elusive, it is known to feature several hormonal disturbances, including hyperandrogenemia, insulin resistance (IR), and hyperinsulinemia. Insulin appears to disrupt all components of the hypothalamus-hypophysis-ovary axis, and ovarian tissue insulin resistance results in impaired metabolic signaling but intact mitogenic and steroidogenic activity, favoring hyperandrogenemia, which appears to be the main culprit of the clinical picture in PCOS. In turn, androgens may lead back to IR by increasing levels of free fatty acids and modifying muscle tissue composition and functionality, perpetuating this IR-hyperinsulinemia-hyperandrogenemia cycle. Nonobese women with PCOS showcase several differential features, with unique biochemical and hormonal profiles. Nevertheless, lean and obese patients have chronic inflammation mediating the long term cardiometabolic complications and comorbidities observed in women with PCOS, including dyslipidemia, metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. Given these severe implications, it is important to thoroughly understand the pathophysiologic interconnections underlying PCOS, in order to provide superior therapeutic strategies and warrant improved quality of life to women with this syndrome.

Figure 1

Interactions among insulin resistance, hyperinsulinemia, and hyperandrogenemia in the etiopathogenesis and progression of polycystic ovary syndrome and related comorbidities. SAT = subcutaneous adipose tissue; VAT = visceral adipose tissue LH = luteinizing hormone; SHBG = sex hormone binding globulin; IGFBP-1 = insulin-like growth factor binding protein-1; IGF-1 = insulin-like growth factor-1; FFA = free fatty acids; TIMF = type I muscle fibers; TIIMF = type II muscle fibers. Although details of the exact etiopathogenesis of PCOS are not clear, it appears to be a combination of environmental and genetic factors, which in consonance favor the development of IR. In turn, IR leads to compensatory Hyperinsulinemia, which substantially augments ovarian androgen synthesis by increasing LH pulse frequency at the hypophysis by stimulating GnRH gene transcription in hypothalamic cells. Insulin also triggers hyperandrogenemia by directly activating mitogenic pathways in ovarian cells and increasing transcription of StAR and several key steroidogenic enzymes. Hyperandrogenemia is the key disruption underlying the typical clinical features of PCOS. In addition, increased ovarian production of androgens may in turn worsen IR, thus perpetuating a vicious cycle of IR-hyperinsulinemia-hyperandrogenemia. Indeed, androgens may not only interfere with insulin signaling directly, but also trigger lipolysis, increasing FFA in circulation, favoring IR. Moreover, androgens seem to diminish highly oxidative and insulin-sensitive TIMF and increase glycolytic and less insulin-sensitive TIIMF, further favoring the development of IR. Additionally, obesity appears to magnify all events in this cycle, by increasing androgen synthesis not only in ovaries, but also in SAT and adrenal glands. Leptin also participates by disrupting ovarian physiology and favoring a chronic systemic inflammatory state. Ultimately, both IR and chronic inflammation thrive on all endocrine-metabolic disturbances pertaining PCOS, predisposing patients to the development of comorbidities, such as type 2 diabetes mellitus and cardiovascular disease.

Figure 2

Insulin signaling in ovarian thecal cells and proposed mechanisms for selective insulin resistance. Solid lines represent well-characterized mechanisms. Dashed lines represent incomplete information or hypothetical mechanisms. (A) Insulin may act in synergy with LH to increase intracellular concentration of cAMP, potentiating PKA activation and subsequent phosphorylation of StAR, favoring steroidogenesis. (B) A hypothetical serine-kinase could unify hyperinsulinemia-hyperandrogenemia in PCOS, as it would inhibit Akt activity, negating the metabolic effects of insulin, while activating steroidogenic enzymes. Furthermore, the mitogenic pathway would be left intact and fully functional, favoring thecal proliferation. (C) Inositolphosphoglycan generation appears to be triggered by INSR-prompted mechanisms independent of signaling molecules within metabolic or mitogenic pathways on insulin signaling. Therefore, inositolphosphoglycans may stimulate steroidogenic activity regardless of metabolic and signaling disturbances typical of systemic insulin resistance.

Figure 3

Mechanisms for obesity-mediated potentiation of hyperandrogenemia in polycystic ovary syndrome. SAT = subcutaneous adipose tissue; VAT = visceral adipose tissue; HHAA = hypothalamus-hypophysis-adrenal-axis; C = cortisol; GCR = glucocorticoid receptor; DHEA = dehydroepiandrosterone; LH = luteinizing hormone; FSH = follicle-stimulating hormone; GC = granulosa cells; TC = teca cells; Ch = carbohydrate; AGE = advanced glycation end products; SHBG = sex hormone binding globulin. In PCOS, obesity may potentiate hyperandrogenemia through several mechanisms. Aside from hyperinsulinemia-mediated effects of IR, increased adiposity leads to faster cortisol metabolism, which results in hyperactivation of the HHAA and thus increased DHEA synthesis. Competitive binding to GCR by GC-produced progesterone derives into diminished cortisol binding to GCR, reinforcing HHAA activation. High adiposity also leads to greater aromatase expression in adipocytes, which allows for increased extraovarian estrogen synthesis. In turn, this causes an elevated LH/FSH ratio, prompting hyperplasia of GC and TC, which then synthesizes greater amounts of progesterone and testosterone, respectively. Hyperleptinemia and leptin resistance result in alterations of LH secretion, as well as downregulation of ovarian collagenases, and promotion of a chronic inflammatory state. Carbohydrate-rich diets may induce oxidative stress in circulating mononuclear blood cells and thus chronic inflammation. Lipid-rich diets have been reported to increase testosterone synthesis and downregulate SHBG synthesis, resulting in hyperandrogenemia. These diets also favor endogenous and exogenous AGE deposition, which results in overall ovarian tissue damage.